TheoverarchingscientificobjectiveoftheCO-SCOREistoadvanceourunderstandingofhowgonadalaging affectsbioenergetics,abdominaladiposity,metabolism,anddiseaserisk,byconductingmechanistically-driven researchacrossthebasic-to-clinicaltranslationalspectrum.CO-SCOREProject2willleveragepreclinical modelsandinterventionstoprovideabi-directional,basic-to-clinicaltranslationalbridgebetweentheclinically relevantstudiesofProject1andthebasicdiscoverystudiesinProject3.Thelong-termobjectiveofProject2 istoworkcollaborativelywithCO-SCOREinvestigatorstodevelopbetterstrategiesfortreatingand preventingthepathologicalconsequencesofgonadalaging,whichdisproportionatelyafflictwomen. Menopauseisassociatedreducedlevelsofphysicalactivity,weightgain,andabdominaladiposity,and predisposeswomentoanumberofage-relateddisordersthatincludeinsulinresistance,diabetes,cancer, osteoporosis,andcardiovasculardisease.StudiesfromProjects1and2inthecurrentcycleoftheaward demonstratedthatestrogen(E2)isanimportantmediatorofthebioenergeticandmetabolicconsequencesof thelossofovarianfunction.Inourpreclinicalmodelofthelossofovarianfunction(surgicalovariectomy,OVX), wehavealsoobservedthatthedeclineinphysicalactivityoccursrapidly,precedeschangesinbodyweight andfatmass,andpredictsthesubsequentgaininweightandfatmass.StudiesfromProject3provide evidencethattheseOVX-inducedchangesinadiposetissuesaretheresultoftheinfiltrationandaccumulation ofbonemarrow-derivedadipocytes(BMDA),whichimpartaproinflammatoryharmfulphenotype.Recent evidencehassuggestedthatelevatedlevelsoffolliclestimulatinghormone(FSH)maycontributetoallofthese detrimentaleffectsthatoccurwiththelossofovarianfunction.InAIM1ofProject2,wemanipulatethese hormonesinapreclinicalmodeltodissecttheindependentandcombinedrolesof?E2and?FSHontheOVX- induceddeclineinspontaneousphysicalactivity(SPA),energybalance,theaccumulationofabdominalfat, andthefunctional,cellular,andmolecularcharacteristicsofadiposetissue.InAIM2ofProject2,weexamine themechanismsbywhichregularexercisecountersOVX-inducedchangesinthefunctional,cellularand molecularcharacteristicsofadiposetissue,includingtheenrichmentofBMDA.Thesestudieswillprovide novelevidenceregardingtherolesof?FSH,?SPA,andadiposetissueenrichmentofBMDAinthemetabolic consequencesofthelossofovarianfunction.Elucidatingthespecificcontributionsofthesefactorstothe detrimentalconsequencesofthelossofovarianfunctionwillleadtoinnovativestrategiesfortheprevention andtreatmentofage-relateddiseasesthataccompanyovarianfailure.